Trial Information

Evaluation of Docosahexaenoic Acid (DHA) for the Treatment of Primary Sclerosing Cholangitis (PSC)

The etiology of Primary Sclerosing Cholangitis (PSC) is unknown. There are no proven
effective therapies and no early markers of the disease to predict which patients with
colitis may be at risk to develop PSC.

Our group has demonstrated an increased prevalence of CFTR alleles (the gene responsible for
Cystic Fibrosis (CF)) in patients with PSC which was correlated with decreased CFTR function
as measured by Nasal Potential Difference Testing. These data suggested that colitis in the
setting of CFTR dysfunction may lead to bile duct inflammation and fibrosis. As proof of
concept, we subsequently demonstrated in cftr-/- mice that (1) colitis leads to the
development of bile duct injury and (2) this is prevented by correction of the CFTR related
fatty acid defect with oral Docosahexaenoic Acid (DHA). Preliminary data in these mice
indicates that low PPAR expression in the liver may predispose to inflammation. One
mechanism by which DHA ameliorates the innate inflammatory response linked to CFTR
dysfunction may be through an increase in PPAR expression.

Based on these data, we hypothesize that CFTR dysfunction may contribute to the pathogenesis
of primary sclerosing cholangitis (PSC). Furthermore, correction of the fatty acid
abnormality and changes in the innate immune response associated with CFTR dysfunction by
oral administration of docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, might
be an effective therapy for patients with PSC.

Immediate Objectives:

To evaluate the effect of DHA therapy on patients with PSC, examining:

Primary Outcome:

• serum alkaline phosphatase

Secondary Outcomes:

- cholangiography

- liver biochemistry (ALT, AST, gamma-glutamyl transferase, bilirubin, albumin,
prothrombin time,)

- fatty acid profile (docosahexaenoic acid, arachidonic acid)

- serum/plasma liver fibrosis markers (hyaluronic acid, tumor necrosis factor-α,
transforming growth factor-ß, type III procollagen peptide)

- innate immune response (peripheral blood monocytes for assessment of cytokine
secretion, lipoxins, and PPAR)

- clinical data on signs and symptoms